Cytokine Stimulation Promotes Glucose Uptake via Phosphatidylinositol-3 Kinase/Akt Regulation of Glut1 Activity and Trafficking

Abstract

Cells require growth factors to support glucose metabolism for survival and growth. It is unclear, however, how noninsulin growth factors may regulate glucose uptake and glucose transporters. We show that the hematopoietic growth factor interleukin (IL)3, maintained the glucose transporter Glut1 on the cell surface and promoted Rab11a-dependent recycling of intracellular Glut1. IL3 required phosphatidylinositol-3 kinase activity to regulate Glut1 trafficking, and activated Akt was sufficient to maintain glucose uptake and surface Glut1 in the absence of IL3. To determine how Akt may regulate Glut1, we analyzed the role of Akt activation of mammalian target of rapamycin (mTOR)/regulatory associated protein of mTOR (RAPTOR) and inhibition of glycogen synthase kinase (GSK)3. Although Akt did not require mTOR/RAPTOR to maintain surface Glut1 levels, inhibition of mTOR/RAPTOR by rapamycin greatly diminished glucose uptake, suggesting Akt-stimulated mTOR/RAPTOR may promote Glut1 transporter activity. In contrast, inhibition of GSK3 did not affect Glut1 internalization but nevertheless maintained surface Glut1 levels in IL3-deprived cells, possibly via enhanced recycling of internalized Glut1. In addition, Akt attenuated Glut1 internalization through a GSK3-independent mechanism. These data demonstrate that intracellular trafficking of Glut1 is a regulated component of growth factor-stimulated glucose uptake and that Akt can promote Glut1 activity and recycling as well as prevent Glut1 internalization.

Autophagy Provides Nutrients but Can Lead to Chop-dependent Induction of Bim to Sensitize Growth Factor–deprived Cells to Apoptosis

“…In contrast, glucose uptake was decreased in control and Bcl-xL cells but not in MyrAkt cells after IL3 withdrawal ( Figure 1E). This is consistent with previous findings showing the inability of Bcl-xL to affect trafficking of the glucose transporter Glut1 and the ability of Akt to promote trafficking of Glut1 to the cell surface (Wieman et al, 2007). …”

“…Glucose uptake was measured as previously described (Wieman et al, 2007), with 5-min incubation of cells with 2-deoxy-d-[ 3 H]glucose (2 Ci/reaction) before separation of internalized glucose from free glucose. Asterisks denote p Ͻ 0.05 by Student's t test.…”

“…When cells were deprived of growth factor, phosphorylation of Akt and mTOR decreased (Wieman et al, 2007;Figure 1A), and expression of the proapoptotic proteins Bim (Zhao et al, 2007) and Puma increased ( Figure 1B). Expression of activated Akt (myristoylated Akt [MyrAkt]), Bcl-xL, or Bcl-2 ( Figure 1C) each prevented cell death ( Figure 1D).…”

“…The phosphoinositide 3-kinase (PI3K)-Akt mammalian target of rapamycin (mTOR) pathway is an important signaling mechanism of many growth factors that maintains nutrient uptake and prevents apoptotic cell death (Vivanco and Sawyers, 2002;Wieman et al, 2007). When cells are deprived of appropriate growth factor stimulation, the loss of PI3K-AktmTOR signaling, glucose transporter localization on the cell surface, and glucose uptake leads to apoptosis or autophagy (Tsujimoto and Shimizu, 2005;Wieman et al, 2007). Unlike the cell death pathway of apoptosis, autophagy is a dualfunction mechanism of bulk cytoplasmic and organelle degradation in lysosomes that can promote cell survival if controlled or can lead to death if excessive.…”

A hierarchical cascade activated by non-canonical Notch signaling and the mTOR–Rictor complex regulates neglect-induced death in mammalian cells

“…[6][7][8][9][10] Akt regulates processes related to proliferation, metabolism, growth, and survival. 11 The kinase modulates cellular responses to environmental cues by regulating the localization of glucose transporters 12 and impinges on mitochondrial integrity and function. 13,14 Akt couples phosphatidylinositol-3 kinase (PI3K) signaling to the nutrient-sensing mammalian target of rapamycin complex-1 (mTORC1) pathway through the phosphorylation of tuberous sclerosis complex-2 (TSC2), 15,16 and is a target of mTOR when the latter is associated with the proteins Rictor, mLST8, and SIN1 to form mTORC2.…”